Modulation by testosterone of an endogenous hERG potassium channel current.
hERG (human ether-a-go-go-related gene) potassium (K+) channels are expressed in a range of tissue types including neuroblastoma cells and the heart, in which hERG K+ current is important for action potential repolarization. Whilst gender differences in cardiac repolarization and the QT interval of the cardiac electrocardiogram are well-established, comparatively little is known about regulation of hERG channels by sex hormones. In this study, whole-cell patch-clamp recordings were made at 37 degrees C from SH-SY5Y human neuroblastoma cells to investigate modulation of endogenous hERG K+ channel current (I(hERG)) by testosterone. Acutely applied testosterone at a physiologically relevant concentration (10 nM) produced a modest (approximately 13-15 %) increase in I(hERG) amplitude, whilst a high concentration (1 microM) slightly decreased I(hERG). The stimulatory effect of testosterone was inhibited by the androgen receptor antagonist flutamide (10 microM) and the PI-3 kinase inhibitor wortmannin (1 microM). Chronic (24 h) application of testosterone also augmented IhERG via flutamide-sensitive receptor activation, without modulation of the current's voltage-dependence. These results demonstrate for the first time that testosterone can stimulate (hERG) K+ channels via activation of classical androgen receptors and implicate PI-3 kinase in the acute response.
Ridley
J M
JM
Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, Bristol, UK.
Shuba
Y M
YM
James
A F
AF
Hancox
J C
JC
D000726:Androgen Antagonists / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D001370:Axonal Transport; D002460:Cell Line; D004558:Electric Stimulation; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists / Q000187:drug effects*; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D018408:Patch-Clamp Techniques; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011944:Receptors, Androgen / Q000187:drug effects; D013696:Temperature; D013739:Testosterone / Q000494:pharmacology*; D000077191:Wortmannin
D000726:Androgen Antagonists; D000730:Androstadienes; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011944:Receptors, Androgen; D013739:Testosterone; D005485:Flutamide; D000077191:Wortmannin